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Naltrexone Hydrochloride And Bupropion Hydrochloride

Class: Anorexigenic Agents, Miscellaneous
Chemical Name: (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrochloride
Molecular Formula: C20H24ClNO4C26H38Cl4N2O2
CAS Number: 16590-41-3
Brands: Contrave

Medically reviewed on Jul 24, 2017

Warning

See full prescribing information for complete boxed warning1

    Warning: Suicidal Thoughts And Behaviors1
  • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.1

  • Monitor for worsening and emergence of suicidal thoughts and behaviors.1

  • Naltrexone hydrochloride and bupropion hydrochloride has not been studied in pediatric patients.1

Introduction

Naltrexone hydrochloride and bupropion hydrochloride is an anorexigenic agent.

Uses for Naltrexone Hydrochloride And Bupropion Hydrochloride

Naltrexone hydrochloride and bupropion hydrochloride has the following uses:

Naltrexone hydrochloride and bupropion hydrochloride is a fixed combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant, and is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).1

Naltrexone hydrochloride and bupropion hydrochloride has the following limitations of use:

The effect of naltrexone hydrochloride and bupropion hydrochloride on cardiovascular morbidity and mortality has not been established.1

The safety and effectiveness of naltrexone hydrochloride and bupropion hydrochloride in combination with other products intended for weight loss, including prescription and over-the-counter drugs and herbal preparations, have not been established.1

Naltrexone Hydrochloride And Bupropion Hydrochloride Dosage and Administration

General

The fixed combination of naltrexone hydrochloride and bupropion hydrochloride is available in the following dosage form(s) and strength(s):

Extended-release tablets: 8 mg naltrexone HCl /90 mg bupropion HCl.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Naltrexone hydrochloride and bupropion hydrochloride dose escalation schedule: 1

Morning Dose

Evening Dose

Week 1

1 tablet

None

Week 2

1 tablet

1 tablet

Week 3

2 tablets

1 tablet

Week 4 – Onward

2 tablets

2 tablets

Cautions for Naltrexone Hydrochloride And Bupropion Hydrochloride

Contraindications

  • Uncontrolled hypertension1

  • Seizure disorders, anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs1

  • Use of other bupropion-containing products1

  • Chronic opioid use1

  • During or within 14 days of taking monoamine oxidase inhibitors (MAOI)1

  • Known allergy to any of the ingredients in naltrexone hydrochloride and bupropion hydrochloride1

  • Pregnancy1

Warnings/Precautions

Suicidal Behavior And Ideation

Naltrexone hydrochloride and bupropion hydrochloride contains bupropion, a dopamine and norepinephrine reuptake inhibitor that is similar to some drugs used for the treatment of depression; therefore, the following precautions pertaining to these products should be considered when treating patients with naltrexone hydrochloride and bupropion hydrochloride.1

Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.1

In placebo-controlled clinical trials with naltrexone hydrochloride and bupropion hydrochloride for the treatment of obesity in adult patients, no suicides or suicide attempts were reported in studies up to 56 weeks duration with naltrexone hydrochloride and bupropion hydrochloride (equivalent to bupropion doses of 360 mg/day). In these same studies, suicidal ideation was reported by 3 (0.20%) of 1515 patients treated with placebo compared with 1 (0.03%) of 3239 treated with naltrexone hydrochloride and bupropion hydrochloride.1

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older.1

The pooled analyses of placebo-controlled trials of antidepressant drugs in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.1

Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects

Age Range

Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated

Increases Compared to Placebo

<18

14 additional cases

18 to 24

5 additional cases

Decreases Compared to Placebo

25 to 64

1 fewer case

≥65

6 fewer cases

No suicides occurred in any of the antidepressant pediatric trials. There were suicides in the adult antidepressant trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.1

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled trials in adults with depression that the use of antidepressants can delay the recurrence of depression.1

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. This warning applies to the fixed combination of naltrexone hydrochloride and bupropion hydrochloride because one of its components, bupropion, is a member of an antidepressant class.1

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.1

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.1

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of anxiety, agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for naltrexone hydrochloride and bupropion hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.1

Neuropsychiatric Adverse Events And Suicide Risk In Smoking Cessation Treatment

Naltrexone hydrochloride and bupropion hydrochloride is not approved for smoking cessation treatment, but serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke.1

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking naltrexone hydrochloride and bupropion hydrochloride and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.1

Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone used in the treatment of opioid dependence. No causal relationship has been demonstrated.1

Seizures

Bupropion, a component of the fixed combination of naltrexone hydrochloride and bupropion hydrochloride, can cause seizures. The risk of seizure is dose-related. The incidence of seizure in patients receiving naltrexone hydrochloride and bupropion hydrochloride in clinical trials was approximately 0.1% vs 0% on placebo. Naltrexone hydrochloride and bupropion hydrochloride should be discontinued and not restarted in patients who experience a seizure while being treated with naltrexone hydrochloride and bupropion hydrochloride.1

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with naltrexone hydrochloride and bupropion hydrochloride. Naltrexone hydrochloride and bupropion hydrochloride is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Caution should be used when prescribing naltrexone hydrochloride and bupropion hydrochloride to patients with predisposing factors that may increase the risk of seizure including: 1

  • history of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia)1

  • excessive use of alcohol or sedatives, addiction to cocaine or stimulants, or withdrawal from sedatives1

  • patients with diabetes treated with insulin and/or oral diabetic medications (sulfonylureas and meglitinides) that may cause hypoglycemia1

  • concomitant administration of medications that may lower the seizure threshold, including other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, systemic steroids1

Recommendations for Reducing the Risk of Seizure

Clinical experience with bupropion suggests that the risk of seizure may be minimized by adhering to the recommended dosing recommendations, in particular:1

  • The total daily dose of the fixed combination of naltrexone hydrochloride and bupropion hydrochloride does not exceed 360 mg of the bupropion component (i.e., 4 tablets per day)1

  • the daily dose is administered in divided doses (twice daily)1

  • the dose is escalated gradually1

  • no more than 2 tablets are taken at one time1

  • Coadministration of naltrexone hydrochloride and bupropion hydrochloride with high-fat meals is avoided 1

  • if a dose is missed, a patient should wait until the next scheduled dose to resume the regular dosing schedule1

Patients Receiving Opioid Analgesics

Vulnerability to Opioid Overdose

Naltrexone hydrochloride and bupropion hydrochloride should not be administered to patients receiving chronic opioids, due to the naltrexone component, which is an opioid receptor antagonist. If chronic opiate therapy is required, naltrexone hydrochloride and bupropion hydrochloride treatment should be stopped. In patients requiring intermittent opiate treatment, naltrexone hydrochloride and bupropion hydrochloride therapy should be temporarily discontinued and lower doses of opioids may be needed. Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after naltrexone hydrochloride and bupropion hydrochloride treatment is discontinued.1

An attempt by a patient to overcome any naltrexone opioid blockade by administering large amounts of exogenous opioids is especially dangerous and may lead to a fatal overdose or life-threatening opioid intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be told of the serious consequences of trying to overcome the opioid blockade.1

Precipitated Opioid Withdrawal

The symptoms of spontaneous opioid withdrawal, which are associated with the discontinuation of opioid in a dependent individual, are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly, the resulting withdrawal syndrome can be severe enough to require hospitalization. To prevent occurrence of either precipitated withdrawal in patients dependent on opioids or exacerbation of a pre-existing subclinical withdrawal symptoms, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting naltrexone hydrochloride and bupropion hydrochloride treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short-acting opioids, and those patients transitioning from buprenorphine or methadone may need as long as 2 weeks. Patients should be made aware of the risks associated with precipitated withdrawal and encouraged to give an accurate account of last opioid use.1

Increase In Blood Pressure and Heart Rate

Naltrexone hydrochloride and bupropion hydrochloride can cause an increase in systolic and/or diastolic blood pressure as well as an increase in resting heart rate. In clinical practice with other bupropion-containing products, hypertension, in some cases severe and requiring acute treatment, has been reported. The clinical significance of the increases in blood pressure and heart rate observed with naltrexone hydrochloride and bupropion hydrochloride treatment is unclear, especially for patients with cardiac and cerebrovascular disease, since patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure were excluded from naltrexone hydrochloride and bupropion hydrochloride clinical trials. Blood pressure and pulse should be measured prior to starting therapy with naltrexone hydrochloride and bupropion hydrochloride and should be monitored at regular intervals consistent with usual clinical practice, particularly among patients with controlled hypertension prior to treatment. Naltrexone hydrochloride and bupropion hydrochloride should not be given to patients with uncontrolled hypertension.1

Among patients treated with naltrexone hydrochloride and bupropion hydrochloride in placebo-controlled clinical trials, mean systolic and diastolic blood pressure was approximately 1 mmHg higher than baseline at Weeks 4 and 8, similar to baseline at Week 12, and approximately 1 mmHg below baseline between Weeks 24 and 56. In contrast, among patients treated with placebo, mean blood pressure was approximately 2 to 3 mmHg below baseline throughout the same time points, yielding statistically significant differences between the groups at every assessment during this period. The largest mean differences between the groups were observed during the first 12 weeks (treatment difference +1.8 to +2.4 mmHg systolic, all p<0.001; +1.7 to +2.1 mmHg diastolic, all p<0.001).1

For heart rate, at both Weeks 4 and 8, mean heart rate was statistically significantly higher (2.1 bpm) in the naltrexone hydrochloride and bupropion hydrochloride group compared with the placebo group; at Week 52, the difference between groups was +1.7 bpm (p<0.001).1

In an ambulatory blood pressure monitoring substudy of 182 patients, the mean change from baseline in systolic blood pressure after 52 weeks of treatment was −0.2 mmHg for the naltrexone hydrochloride and bupropion hydrochloride group and −2.8 mmHg for the placebo group (treatment difference, +2.6 mmHg, p=0.08); the mean change in diastolic blood pressure was +0.8 mmHg for the naltrexone hydrochloride and bupropion hydrochloride group and −2.1 mmHg for the placebo group (treatment difference, +2.9 mmHg, p=0.004).1

A greater percentage of subjects had adverse reactions related to blood pressure or heart rate in the naltrexone hydrochloride and bupropion hydrochloride group compared to the placebo group (6.3% vs 4.2%, respectively), primarily attributable to adverse reactions of Hypertension/Blood Pressure Increased (5.9% vs 4%, respectively). These events were observed in both patients with and without evidence of preexisting hypertension. In a trial that enrolled individuals with diabetes, 12% of patients in the naltrexone hydrochloride and bupropion hydrochloride group and 6.5% in the placebo group had a blood pressure-related adverse reaction.1

Allergic Reactions

Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue naltrexone hydrochloride and bupropion hydrochloride and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, urticaria, chest pain, edema, or shortness of breath) during treatment.1

Arthralgia, myalgia, fever with rash, and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.1

Hepatotoxicity

Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone exposure during naltrexone clinical trials and in postmarketing reports for patients using naltrexone. Transient, asymptomatic hepatic transaminase elevations were also observed. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including preexisting alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury.1

Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of naltrexone hydrochloride and bupropion hydrochloride should be discontinued in the event of symptoms and/or signs of acute hepatitis.1

In naltrexone hydrochloride and bupropion hydrochloride clinical trials, there were no cases of elevated transaminases greater than 3 times the upper limit of normal (ULN) in conjunction with an increase in bilirubin greater than 2 times ULN.1

Activation of Mania

Bupropion, a component of the fixed combination of naltrexone hydrochloride and bupropion hydrochloride, is a drug used for the treatment of depression. Antidepressant treatment can precipitate a manic, mixed, or hypomanic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating naltrexone hydrochloride and bupropion hydrochloride, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Naltrexone hydrochloride and bupropion hydrochloride is not approved for use in treating bipolar depression. No activation of mania or hypomania was reported in the clinical trials evaluating effects of naltrexone hydrochloride and bupropion hydrochloride in obese patients; however, patients receiving antidepressant medications and patients with a history of bipolar disorder or recent hospitalization because of psychiatric illness were excluded from naltrexone hydrochloride and bupropion hydrochloride clinical trials.1

Angle-closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including bupropion, a component of naltrexone hydrochloride and bupropion hydrochloride, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.1

Potential Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Antidiabetic Therapy

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas). Measurement of blood glucose levels prior to starting naltrexone hydrochloride and bupropion hydrochloride and during naltrexone hydrochloride and bupropion hydrochloride treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for antidiabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting naltrexone hydrochloride and bupropion hydrochloride, appropriate changes should be made to the antidiabetic drug regimen.1

Specific Populations

Pregnancy

Pregnancy Category X.1

Risk Summary: Naltrexone hydrochloride and bupropion hydrochloride is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.1

Clinical Considerations: A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.1

Human Data: There are no adequate and well-controlled studies of naltrexone hydrochloride and bupropion hydrochloride in pregnant women. In clinical studies, 21 (0.7%) of 3024 women became pregnant while taking naltrexone hydrochloride and bupropion hydrochloride: 11 carried to term and gave birth to a healthy infant, 3 had elective abortions, 4 had spontaneous abortions, and the outcome of 3 pregnancies were unknown.1

Data from the international bupropion pregnancy registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1213 first trimester exposures) did not show an increased risk for malformations overall.1

No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international pregnancy registry was 1.3% (9 cardiovascular malformations out of 675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6853 infants with cardiovascular malformations and 5763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.1

Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted odds ratio [OR] = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO.1

Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.1

For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.1

Animal Data: Reproduction and developmental studies have not been conducted for the combined products naltrexone and bupropion in naltrexone hydrochloride and bupropion hydrochloride. Safety margins were estimated using body surface area exposure (mg/m2) based on a body weight of 100 kg.1

Separate studies with bupropion and naltrexone have been conducted in pregnant rats and rabbits.1

Naltrexone administered orally has been shown to increase the incidence of early fetal loss in rats administered ≥30 mg/kg/day (180 mg/m2/day) and rabbits administered ≥60 mg/kg/day (720 mg/m2/day), doses at least 15 and 60 times, respectively, the maximum recommended human dose [MRHD] of the naltrexone component in naltrexone hydrochloride and bupropion hydrochloride on a mg/m2 basis. There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (approximately 100 and 200 times the recommended therapeutic dose, respectively, on a mg/m2 basis). Rats do not form appreciable quantities of the major human metabolite, 6-beta-naltrexol; therefore, the potential reproductive toxicity of the metabolite in rats is not known.1

Bupropion was administered orally in studies conducted in rats and rabbits at doses up to 450 and 150 mg/kg/day, respectively (approximately 20 and 15 times the MRHD, respectively, of the bupropion component in naltrexone hydrochloride and bupropion hydrochloride on a mg/m2 basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately 2 times the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater (approximately 5 times the MRHD of the bupropion component in naltrexone hydrochloride and bupropion hydrochloride on a mg/m2 basis). When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 15 times the MRHD of the bupropion component in naltrexone hydrochloride and bupropion hydrochloride on a mg/m2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.1

Lactation

The constituents and metabolites of naltrexone hydrochloride and bupropion hydrochloride have been shown to be secreted in human milk. Transfer of naltrexone and 6-beta-naltrexol into human milk has been reported with oral naltrexone. Bupropion and its metabolites are also secreted in human milk. Naltrexone hydrochloride and bupropion hydrochloride is not recommended for nursing mothers.1

Pediatric Use

The safety and effectiveness of naltrexone hydrochloride and bupropion hydrochloride in pediatric patients below the age of 18 have not been established and the use of naltrexone hydrochloride and bupropion hydrochloride is not recommended in pediatric patients.1

Geriatric Use

Of the 3239 subjects who participated in clinical trials with naltrexone hydrochloride and bupropion hydrochloride, 62 (2%) were 65 years and older and none were 75 years and older. Clinical studies of naltrexone hydrochloride and bupropion hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Older individuals may be more sensitive to the central nervous system adverse effects of naltrexone hydrochloride and bupropion hydrochloride. Naltrexone and bupropion are known to be substantially excreted by the kidney, and the risk of adverse reactions to naltrexone hydrochloride and bupropion hydrochloride may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Naltrexone hydrochloride and bupropion hydrochloride should be used with caution in patients over 65 years of age.1

Renal Impairment

A dedicated pharmacokinetic study has not been conducted for naltrexone hydrochloride and bupropion hydrochloride in subjects with renal impairment. Based on information available for the individual constituents, systemic exposure is significantly higher for bupropion and metabolites (two- to threefold), and naltrexone and their metabolites in subjects with moderate-to-severe renal impairment. Therefore, the maximum recommended daily maintenance dose for naltrexone hydrochloride and bupropion hydrochloride is 2 tablets (1 tablet each morning and evening) in patients with moderate or severe renal impairment. Naltrexone hydrochloride and bupropion hydrochloride is not recommended for use in patients with end-stage renal disease. There is a lack of adequate information to guide naltrexone hydrochloride and bupropion hydrochloride dosing in patients with mild renal impairment.1

Hepatic Impairment

Naltrexone hydrochloride and bupropion hydrochloride has not been evaluated in subjects with hepatic impairment. Based on information available for the individual constituents, systemic exposure is significantly higher for bupropion and metabolites (two- to threefold), and naltrexone and their metabolites (up to tenfold higher) in subjects with moderate-to-severe hepatic impairment. Therefore, the maximum recommended daily dose of naltrexone hydrochloride and bupropion hydrochloride is 1 tablet in the morning in patients with hepatic impairment.1

Common Adverse Effects

  • Most common adverse reactions (greater than or equal to 5%): nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly.1

  • Drugs Metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants, (e.g., selective serotonin reuptake inhibitors and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and type 1C antiarrhythmics (e.g., propafenone and flecainide): Consider dose reduction when using with naltrexone hydrochloride and bupropion hydrochloride.1

  • Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels.1

  • Concomitant Treatment with CYP2B6 Inhibitors (e.g., ticlopidine or clopidogrel) can increase bupropion exposure. Do not exceed 1 tablet twice daily when taken with CYP2B6 inhibitors.1

  • CYP2B6 Inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) may reduce efficacy by reducing bupropion exposure; avoid concomitant use.1

  • Drugs that Lower Seizure Threshold: Dose naltrexone hydrochloride and bupropion hydrochloride with caution.1

  • Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with naltrexone hydrochloride and bupropion hydrochloride.1

  • Drug-Laboratory Test Interactions: naltrexone hydrochloride and bupropion hydrochloride can cause false-positive urine test results for amphetamines.1

Actions

Mechanism Of Action

Naltrexone hydrochloride and bupropion hydrochloride has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on 2 separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects of naltrexone hydrochloride and bupropion hydrochloride leading to weight loss are not fully understood.1

Advice to Patients

Patient Counseling Information

See FDA-Approved Patient Labeling.1 The instructions provided in the Medication Guide should be discussed with patients.1

Patients should be advised to take naltrexone hydrochloride and bupropion hydrochloride exactly as prescribed. Patients should be instructed to follow the dose escalation schedule and not to take more than the recommended dose of naltrexone hydrochloride and bupropion hydrochloride.1

Patients should be made aware that naltrexone hydrochloride and bupropion hydrochloride contains the same active ingredient (bupropion) found in certain antidepressants and smoking cessation products (including, but not limited to, Wellbutrin, Wellbutrin SR, Wellbutrin XL, Aplenzin, and Zyban) and that naltrexone hydrochloride and bupropion hydrochloride should not be used in combination with any other medications that contain bupropion.1

Patients should be advised that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking bupropion. Instruct patients to discontinue naltrexone hydrochloride and bupropion hydrochloride and contact a healthcare professional if they experience such symptoms.1

Patients should be advised of the potential serious risks associated with the use of naltrexone hydrochloride and bupropion hydrochloride, including suicidality, seizures, and increases in blood pressure or heart rate.1

Patients should be advised to call their healthcare provider to report new or sudden changes in mood, behavior, thoughts, or feelings.1

Patients should be advised that taking naltrexone hydrochloride and bupropion hydrochloride can cause mild pupillary dilation, which in susceptible individuals can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy) if they are susceptible.1

Patients should be educated on the symptoms of hypersensitivity and to discontinue naltrexone hydrochloride and bupropion hydrochloride if they have a severe allergic reaction to naltrexone hydrochloride and bupropion hydrochloride.1

Patients should be told that naltrexone hydrochloride and bupropion hydrochloride should be discontinued and not restarted if they experience a seizure while on treatment.1

Patients should be advised that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Patients should be advised to minimize or avoid use of alcohol.1

Patients should be advised that if they previously used opioids, they may be more sensitive to lower doses of opioids and at risk of accidental overdose should they use opioids after naltrexone hydrochloride and bupropion hydrochloride treatment is discontinued or temporarily interrupted.1

Patients should be advised that because naltrexone, a component of the fixed-combination tablet can block the effects of opioids, they will not perceive any effect if they attempt to self-administer any opioid drug in small doses while on naltrexone hydrochloride and bupropion hydrochloride. Further advise patients that the attempt to administer large doses of any opioid or to bypass the blockade while on naltrexone hydrochloride and bupropion hydrochloride may lead to serious injury, coma, or death.1

Patients should be off all opioids for a minimum of 7 to 10 days before starting naltrexone hydrochloride and bupropion hydrochloride in order to avoid precipitation of withdrawal. Advise patients they should not take naltrexone hydrochloride and bupropion hydrochloride if they have any symptoms of opioid withdrawal.1

Patients should be advised to call their healthcare provider if they experience increased blood pressure or heart rate.1

Patients should be advised to notify their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs. Concern is warranted because naltrexone hydrochloride and bupropion hydrochloride and other drugs may affect each other’s metabolism.1

Patients should be advised to notify their healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding during therapy.1

Patients with type 2 diabetes mellitus on antidiabetic therapy should be advised to monitor their blood glucose levels and report symptoms of hypoglycemia to their healthcare provider(s).1

Patients should be advised to swallow naltrexone hydrochloride and bupropion hydrochloride tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Naltrexone Hydrochloride And Bupropion Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

8 mg naltrexone hydrochloride, 90 mg bupropion hydrochloride

Contrave

Orexigen Therapeutics Inc.

AHFS Drug Information. © Copyright 2018, Selected Revisions July 24, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Orexigen Therapeutics, Inc.. Contrave (naltrexone hydrochloride and bupropion hydrochloride) extended-release tablets prescribing information. 2017 May. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b

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